A Phase 1 SBIR program of pre-clinical development is proposed focusing on a novel rapid-acting insulin analog for the treatment of diabetes mellitus. Designated Insulin-Cl, our product is a derivative of insulin lispro (the active component of HumalogTM) containing a single chloro-substitution within the aromatic ring of a conserved phenylalanine in the B-chain (PheB24). Insulin-Cl retains the interchange of residues B28 and B29 (substitutions ProB28 .Lys and LysB29.Pro) that confers upon HumalogTM its rapid absorption following subcutaneous injection. Insulin-Cl offers to patients the potential advantages of (i) greater shelf life and stability to degradation at temperatures above room temperature;and (ii) possible formulation as a zinc-free solution to provide ultra- rapid absorption. Current meal-time insulin analogs such as HumalogTM and NovalogTM are less stable than human insulin and must be formulated as zinc insulin hexamers;as a consequence, absorption is in principle not as rapid as could be provided by a zinc-free formulation. Ultra-rapid absorption of Insulin-Cl may offer added patient convenience and also enhanced safety in closed-loop "smart pumps" coupled to glucose sensors. We seek to test candidate formulations of Insulin-Cl and to assess its in vivo potency and pharmacokinetics in animal models. Insulin-Cl was invented at Case Western Reserve University and is being developed under license to Thermalin Diabetes, Inc. The principal investigator, who brings to this application four decades of experience in pharmacetical studies of insulin formulations, was co-inventor of insulin lispro. PUBLIC HEALTH RELEVANCE: Diabetes is an increasingly prevalent disease in the developed and developing worlds;patients seek greater convenience, improved glycemic control, and fewer adverse side-effects, all of which result in greater compliance and lower healthcare costs. This project will complete pre- clinical development of Insulin-Cl, a potentially ultra-stable and ultra-rapid acting insulin analog which could conveniently be stored without refrigeration and taken closer to meal time and could cause less post-meal glucose deficiency.